This invention relates specifically to anti-inflammatory and antiallergic compounds, having therapeutic use in various diseases, most importantly for patients suffering from pulmonary diseases, including asthma and bronchitis, from dermal diseases, including urticaria and atopic dermatitis and from gastro-intestinal disorders including gastric irritation and enteritis.
The compounds described in this invention are metabolites of ketotifen (4-(1-methyl-4-piperidyline)-4H-benzo(4,5) cyclohepta-(1,2-b) thiophene-10-one). Due to serious sedative side effects that are related to ketotifen, that compound has limited therapeutic usefulness.
Ketotifen is metabolized in the body along various pathways:

The metabolite norketotifen (also called nor-ketotifen) is formed by demethylation of ketotifen:

The metabolites 10-hydroxy-ketotifen and 10-hydroxy-norketotifen are formed by reduction of the ketotifen and norketotifen molecules, respectively.

Other metabolites of ketotifen are also formed in the body after administration of ketotifen. Thus, the ketotifen molecule can undergo N-glucuronidation and be converted into N-oxide ketotifen. The hydroxylated isomers can be further metabolized to 10-hydroxy-glucuronidates. Other metabolites may be formed as well and the metabolic pathways are different in various species and may also be different between infants and adults.
No published pharmacological studies of the racemates or the isomers of norketotifen, 10-hydroxy-ketotifen or 10-hydroxy-norketotifen are known to us. Pharmacological properties of the isomers of ketotifen have been described by Polivka et al.: 4H-benzo(4,5)cyclohepta(1,2-b)thiophenes and 9,10-dihydro derivatives-sulfonium analogues of pizotifen and ketotifen; chirality of ketotifen; synthesis of the 2-bromo derivative of ketotifen. Collect. Czech. Chem. Commun. 1989, 54, 2443-2469.